ANTIHYPERTENSIVE
AGENTS(Unit Objective - Student should able to understand the Chemistry of various classes of antihypertensive agents.)
Prof. S.G. JAWARKAR
Dept of pharmaceutical Chemistry
Vidyabharati college of Pharmacy, Amravati.
HYPERTENSIONIt is defined as a physiologic condition where there is an increase in the arterial blood pressureabove normal.
•Normal B.P is 120/80 mm Hg.
•An individual is hypertensive when
B.P is >140/90 mm Hg.
Hypotension may be defined as a physiologic state where there is a
HYPERTENSION IS DEVIDED IN TO 2 TYPES:
1.PRIMARY HYPERTENSION OR ESSENTIAL HYPERTENSION
1.SECONDARY HYPERTENSION OR MALIGNANT HYPERTENSION.
In PRIMARY OR ESSENTIAL HYPERTENSION In majority of casses where etiology
Is unknown cause and is known as primary hypertension.
The following factors may contribute to elevate of B.P
•Dietary intake of more sodium and less potassium.
In some cases primary hypertension may be herediatary.
Advancement of age.
Decreased vascular synthesis of Nitric oxide (No)( is useful in vasodialatation)
In SECONDARY HYPERTENSION where etiology can be identified.
Secondary hypertension is due toRenal disease (kidney disorders ( Chronic glomerular nephritis.)Adrenal disease (endocrine disorders)
Pheochromocytoma (tumour on adrenal medulla) which secretes excessive
catechol amines like adrenaline and nor adrenaline)
Hyper aldosteronism.Muscular disorders:
Contraction (narrowing)of aorta.
Renal artery stenosis(narrowing of artery )
Toxemia of pregnancy (presence of toxins in the blood stream)
Encephalitis(inflammation of the briain)
Increased intra cranial pressure.
Thyrotoxicosis(toxic condition caused by over activity of thyroid gland)
oral contraceptives.
CAUSES OF HYPERTENSION
Classification(category ofHypertension)
Systolic Blood Pressure (mmHg)
DiastolicBlood
Pressure (mmHg)
Normal (B.P) 120 and 80
Prehypertension 121-139 or 81-89
140-159 or 90-99Stage 1 (mild) hypertension
Stage 2 hypertension (moderate)
160-179 or 100-109
6Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.
Stage III (severe) 180-209 110-119.
>210 >120.Stage iV (very
severe)
On etiological basis hypertension is divided into two types
1.Primary hypertensionA definite cause is not known in primary hypertension.
Following factors may contribute to elevation of B.P.•Dietary intake of more sodium and less potassium.•Decrease in vascular synthesis of nitric oxide responsible for vasodilation.•In some cases it may be heriditary.
2.Secondary HypertensionIn some cases Hypertension may be secondary to other diseases like
a.Endocrine disorders•Pheochromocytoma•Hyperaldosteronism b.Chronic glomerular nephritis c.Muscular disorders•Contraction of aorta•Renal artery stenosis
Classification of antihypertensive agentsHypertension = Disease of the blood vessels
Vascular biology altered
Treat the vasculature
Therapeutic options
Beta
BlockersACE DiureticsARB CCB Others
Adapted from Vascular Biology Working Group, University of Florida
College of Medicine, Carl Pepine, MD, Director10
The Renin-Angiotensin Cascade and the 3 Available Approaches to
Pharmacologic Inhibition of Production or Action of Angiotensin II. Direct
renin inhibitors (DRI), angiotensin-converting enzyme inhibitors (ACEI),
and angiotensin (AT) type 1 receptor blockers (ARB).
Drugs interacting with Renin-Angiotensin system
Depending on chemical classification
ACE inhibitors
Sulphydryl
E.g:CaptoprilDicarboxylate
E.g:Enalapril
,Lisinopril
Phosphate
E.g:Fosinopril
CAPTOPRIL
ENALAPRIL
FOSINOPRIL
Structure activity relationship[SAR]
RGroups that bind
to Zn+2 ion
1R
CH C (N
O
Ring)
Essential for stabilisation
Methyl group resembles side
chain of alanine
Enhances the potency of the
compound
Sulfhydryl group leads to
shorter duration of
action
n-butylamine in dicarboxylate
containing componds orally
active.
Mechanism ofaction
They inhibit ACE which is involved in the conversion of AngI
to Ang II.
•Which is a potent vasoconstrictor.
Adverse effects
•Dry cough
•Dysgysia
•Skin rashes
•Foetal toxicity
Uses
First choice in treatment of Hypertension.
In left ventricular failure
In diabetic nephropathy
In myocardial infarction
ACE InhibitorsCAPTOPRIL:-
Mechanism of Action:
It decreases angiotensin II and increase bradykinin levels. Vasodilation is a
result of decreased vasocontriction from diminished levels of angiotensin II
and enhanced vasodilation from increase bradykinin. By reducing circulating
angiotensin II levels, ACE inhibitors also decrease the secretion of
aldosterone, resulting in decreased sodium and water retention.
Captopril, 1-[(2S)-3-mercapto-2-methyl-1-oxopropionyl]proline (Capoten), blocks
the conversion of angiotensinI to angiotensin II by inhibiting the
convertingenzyme. The rational development of captopril as an inhibitorof ACE
was based on the hypothesis that ACE and carboxypeptidaseA functioned by
similar mechanisms. It was noted that d-2-benzylsuccinic acid7 was a potent
inhibitor of carboxypeptidase A, but not ACE. By use of this small
•Benazepril (Lotensin®)
•Captopril (Capoten®)
•Fosinopril (Monopril®)
•Lisinopril
(Prinivil®,Zestril®)
•Enalapril (Vasotec®)
•Quinapril (Accupril®)
•Ramipril (Altace®)
•Trandolapril (Mavik®)
ACE inhibitors
Angiotencin receptor Antagonists
LOSARTAN:-
It is a competitive antagonist and inverse agonist, it is more selective
for AT1 than for AT2 recetor it does not block any other receptor or ion
channel except thromoxane A2 receptor .
Other action of ARBs blocker are vasocontriction, central and
peripheral sympathetic stimulation, release of aldosterone and Adr
from adrenals, renal action promoting salt and water reabsorption,
central action like thirst, vasopressin release and growth promoting
action on heart and blood vessels.
CH 2
N
N H
X
Acidic group
STRUCTURE ACTIVITY RELATIONSHIP[SAR]
Essential for activity to
mimic Asp1 carboxylate of
Ang-II
Substituted with
ketones,cooH forms
Ionic,dipole-dipole helps
drug to interact with
AT1
Require to mimic the His side
chain of Angiotensin-II
Mechanism ofaction
They act by blocking the Angiotensin I which regulates the
effects of angiotensin on B.P,heart and sodium and water
balance.
Adverse effects
HyperkalaemiaAngioedemaFoetal toxicityGidisturbances
Uses
In treatment of hypertension as an alternative to
ACE Inhibitors.
Valsartan (Diovan®)
Telmisartin (Micardis®)
Candesartan (Atacand®)
Losartin (Cozaar®)Irbesartin (Avapro®)
Angiotensin receptor blockers
Diuretics
•
28
Diuretics ("water pills") increase the
kidneys' excretion of salt (sodium) and
water, decreasing the volume of fluid in
the bloodstream and the pressure in the
arteries. Diuretics are the oldest and
most studied antihypertensive agents.
Thiazide
chlorthalidone, hydrochlorothiazide (HCTZ),
indapamide, metolazone
Loop
bumetanide, furosemide, torsemide
Potassium-sparing
amiloride, triamterene
Aldosterone antagonists
eplerenone, spironolactone
CLASSIFICATION
Thiazide Diuretics
D o s e in morning to avoid nocturnaldiuresis
M o r e effective antihypertensives than loop diuretics
. Chlorthalidone 1.5 to 2 times as potent as HCTZ
Adverse effects
• hypokalemia
•
•
•
hypomagnesemia
hypercalcemia
sexual dysfunction
lithium toxicity with
Concurrent adminstration.
3131
Loop Diuretics
D o s e in AM or afternoon to avoid nocturnaldiuresis
Higher doses may be needed for patients with severely decreased glomerular filtration rate or heart failure
Furosemide
Adverse effects:
hypokalemia,
hypomagnesemia,
hypocalcemia
32
Mechanism of Action
inhibit Na+ and Cl- transporter in distal convoluted
tubules
increased Na+ and Cl- excretion
weak inhibitors of carbonic anhydrase, increased
HCO3- excretion
increased K+/Mg2+
excretion
decrease Ca2+ excretion
Potassium-sparing Diuretics
Dose in AM or afternoon to avoid nocturnal diuresis
Generally reserved for diuretic-induced hypokalemia
patients
Weak diuretics, generally used in combination with
thiazide diuretics to minimize hypokalemia
Adverse effects:
m a y cause hyperkalemia especially in combination with an
ACE inhibitor, angiotensin-receptor blocker or potassium
supplements
avoid in patients with diabetes
35
Aldosteroneantagonists
Dose in AM or afternoon to avoid nocturnaldiuresis
Adverse effects:
m ay cause hyperkalemia especially in combination withACE inhibitor, angiotensin-receptor blocker or potassium supplements
Gynecomastia: up to 10% of patientstaking spironolactone
36
Calcium channel blockers
Benzothiazepines
Eg:Diltiazem
Depending upon their chemical structure
Diphenylalkylamines
Eg:Verapamil
1,4-dihydropyridines
Eg:Nifedipine
Diaminopropanol ether
Eg:Bepridil
Verapamil Diltiazem
NifedipineNifedipine
DRUGS Mode of action
Adverse Drug reactions
Uses
Diltiazem Acts by inhibiting Voltage sensitive Calcium channels in myocardium and vascular smooth muscles.
oConstipation
oDizziness
oOedema
oIn
arrythmias
oIn Angina
oFlushing oOedema
•In Angina
In Arrythmias
Verapamil
Nifedipine oTachycardia In Angina
Calcium channel blockers
•Idradipine (DynaCirc®)
•Nicardipine (Cardene®)
•Nisoldipine (Sular®)
•Felodipine (Plendil®)
•Amlodipine (Norvasc®)
Centrally acting sympatholytics
Mechanism of action
Methyldopa is an α2 adrenergic receptor agonist acts centrally by
decreasing the sympathetic outflow which inturn lowers B.P.
Methyldopa
Adverse effects
Sedation and drowsyness
Constipation
Gynacomastia
Sexual impotense
Uses
Treat of Hypertension in combination
With diuretics.
clonidine
Mode of action:
Its acts by stimulating α2-adrenergic receptros and thereby reducing sympathetic outflow and noradrenaline release
Clonidine Hydrochloride.
2-[(2,6-dichlorophenyl)imino]imidazolidine monohydrochloride(Catapres), was
synthesized in 1962 as a derivative of the known -sympathomimetic drugs
naphazoline and tolazoline, potential nasal vasoconstrictors, but instead it proved to
be effective in the treatment of mild-to-severe hypertension. Clonidine
hydrochloride acts by both peripheral and central mechanisms in the body to affect
blood pressure. It stimulates the peripheral -adrenergic receptors to produce
vasoconstriction, resulting in a brief period of hypertension. Clonidine
hydrochloride acts centrally to inhibit the sympathetic tone and cause hypotension
that is of much longer duration than the initial hypertensive effect. Administration of
clonidine hydrochloride thus produces a biphasic change in blood pressure,
beginning with a brief hypertensive effect and followed by a hypotensive effect that
persists for about 4 hours. This biphasic response is altered by dose only. Larger
doses produce a greater hypertensive effect and delay the onset of the hypotensive
properties of the drug.
I n moderate to severe hypertension
F o r withdrawl therapy of alcohol opioids
To diagnose pheochromocytoma
Sedation anddrowsiness
Dryness of mouthand nase
Constipation
Bradycardia
Adverse drug reaction uses
PrazosinPrazosin phentolamine
Adrenergic receptorantagonist
Clonidine Hydrochloride.
2-[(2,6-dichlorophenyl)imino]imidazolidine monohydrochloride(Catapres), was
synthesized in 1962 as a derivative of the known -sympathomimetic drugs
naphazoline and tolazoline, potential nasal vasoconstrictors, but instead it proved to
be effective in the treatment of mild-to-severe hypertension. Clonidine
hydrochloride acts by both peripheral and central mechanisms in the body to affect
blood pressure. It stimulates the peripheral -adrenergic receptors to produce
vasoconstriction, resulting in a brief period of hypertension. Clonidine
hydrochloride acts centrally to inhibit the sympathetic tone and cause hypotension
that is of much longer duration than the initial hypertensive effect. Administration of
clonidine hydrochloride thus produces a biphasic change in blood pressure,
beginning with a brief hypertensive effect and followed by a hypotensive effect that
persists for about 4 hours. This biphasic response is altered by dose only. Larger
doses produce a greater hypertensive effect and delay the onset of the hypotensive
properties of the drug.
Drugs Mode ofaction
Adverse drug
reactionUses
prazosin
It acts by
selective blocking of α-1 receptors in the peripheralblood vessels leading to vasodilation
First dose effect:Postural hypotension and syncopeDrowsinessHeadacheNasal congestion
In the treatment of moderate to serve hypertension in combinaton with a β-blocker and a diuretic
Adrenergic receptorantagonists
α-blockers
Drugs Mode of action
Adverse drug
reactionUses
Phentolamine
It blocks both α1 and α2-receptors leading to vasodilation and increase in noradrenali ne release
Hypotensio nTachycardiaIncrease in gastric acid secretion
Pheochrom ocytoma
PROPANOLOL ATENOLOL
LABETOLOL
β-adrenergic Blockers
PROPRANOLOL
Drugs Mode of
action
Adverse drug effects
Uses
Propanolol Inhibits sympathetic activity by blocking β1 and β2 receptors
•Fatigue
•Bradycardi a•Hypoglyce mia
•In angina•In myocardial infarction•In arrythmias
β-adrenergic Blockers
Drug Mode of action
Adverse drug reactions
Uses
Atenolol Inhibit •Fatigue In anginaSympathetic •Bradycardia Inactivity by arrythmiaselective sblockage ofβ1 receptors.
Drug Mode of action
Adverse effects
Uses
•Carvedilol
•Labetalol
They block β and α1 receptor there by inhibit sympathetic activity.
dysfunction
•Dry mouth •Cavedilol-•Gidisturbances CHF
•Sexual•Labetalol-Emergencies
MINOXIDIL HYDRALAZINE
Direct vasodilators
Drug Mode of action
Adverse effects
Uses
Minoxidil It opens the
potassium channels and causes hyperpolari zation.
•Tachycardia
•Fluid•In treatment
retension of
•Hypertricho Baldness sis
Direct Vasodilators
Drug Mode of
action
Adverse
effects
Uses
Hydralazine Direct relaxation of vascular smooth muscles by stimulating cGMP
•Flushing•Tachycardia
•Fluid retension
Emergencies
"Saunders said. "Doctors are using ACE inhibitors,
Calcium channel blockers, Beta-blockers, Angiotensin-
receptor blockers (ARBs), Alpha-blockers and low-dose
diuretics in ways that don't cause the sexual
complications and other side effects of older therapies.
Also, these new drugs only need to be taken once a day,
instead of two or three times a day. This is a lot easier for
patients." .
We need to make sure that we eat eight servings of fruits
and vegetables a day, and get more exercise. We need to
get ourselves and our children away from the television
sets and the computers, and start them exercising early in
their lives."
CONCLUSION
Acknowledgement
I would like to express my special thanks of gratitude
to Power point presentation by
PROF. RAVISANKAR, Vigyan Pharmacy
college,Valdlamudi, Guntur Dist. A.P.
REFERENCES
Wilson and Gisvolds Text book of Organic Medicinal And
Pharmaceutical chemistry
Principles of Medicinal chemistry Dr.S.S.Kadam
Dr.K.R..Mahadik
Dr.K.G.Bothara
Text book of Medicinal chemistry vol-1 K.Ilango
P.Valentine
Principles of Medicinal chemistry by William foeye
Advanced practical Medicinal chemistry by Ashutoshkar
Profiles in drug synthesis vol-1 Dr.v.N.GOGTE
The organic chemistry of drug synthesis vol-3 DANIEL
LEDNISER,LESTER .A.MITSCHER
Medicinal chemistry D.SRIRAM,P.YOGEESWARI
Essentials of Medicinal chemistry II Edition –
ANDREJUS KAROLKOVAS
Power point presentation by PROF. RAVISANKAR,
Vigyan Pharmacy college,Valdlamudi, Guntur Dist. A.P.